Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies.[unreadable] [unreadable] Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial.[unreadable] [unreadable] Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation.[unreadable] [unreadable] Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock. This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The lack of rhAPC efficacy in patients with a low risk of death was confirmed in the ADDRESS trial.[unreadable] [unreadable] The administration of L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful. L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients.[unreadable] [unreadable] Intra-aortic balloon counterpulsation was found to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock. This result suggests that counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock.[unreadable] [unreadable] An investigation of the hypothalamic-pituitary-adrenal axis and potential benefits of glucocorticoids and mineralocorticoids is ongoing in mouse and canine models of septic shock. These experiments are aimed at defining issues of dose and timing as well as glucocorticoid and mineralicorticoid effects at the cellular level. The more general topic of nuclear receptor transrepression of inflammatory responses to sepsis is being explored both in vitro and in vivo.